A defining feature of Mycobacterium tuberculosis (Mtb) is its ability to manifest as a latent infection that can last for many years. Latent tuberculosis affects nearly 2 billion people, and in much of the world, reactivating Mtb is responsible for the vast majority of active tuberculosis (TB). In this way, latency and reactivatio shape Mtb pathogenesis and transmission and are major impediments to TB control. The bacterial signaling mechanisms and effectors driving the switch between latency and reactivation (the latency switch) are almost entirely unknown. The signal transduction that underpins transitions of this type in other bacteria propagates through phosphorylation pathways. Using a highly reproducible, defined in vitro model of hypoxia followed by reaeration to model latency and reactivation in Mtb, we now show that the Ser/Thr protein kinase PknB and its cognate phosphatase, PstP, are major regulators of replication in response to oxygen and show that PknB is regulated by a new Mtb posttranslational modification, protein Tyr phosphorylation. Based on these data, we hypothesize that Ser/Thr and Tyr phosphosignaling control the Mtb latency switch. By defining a phosphosignaling system- PknB and PstP- that controls the physiologic response of Mtb to shifting oxygen tension, we provide an opportunity to identify the relevant downstream substrates and effectors that execute hypoxia adaptations. These findings will uncover signaling pathways and effectors that control latency and reactivation.